Epilepsy is a common chronic neurological condition that affects over 50 million people worldwide, including approximately three million Americans. Although effective anticonvulsant drugs have been available since the early 1900's, significant unmet medical needs remain. Current estimates indicate that 25% of people suffering from epilepsy receive no effective treatment for their seizures from today's available drugs. Of those that do, approximately 15% report inadequate treatment and another 20% have intractable seizures. Serious toxicities (Stevens Johnson syndrome, metabolic acidosis, aplastic anemia), reduced bone mineral density and osteoporosis, and teratogenicity are concerns with currently marketed antiepileptic drugs.
Frequently identified causes of epileptic seizures include stroke, injuries, poisoning (alcoholism), and systemic illnesses during pregnancy or brain injuries during childbirth. However, for 65-75% of children and 50% of adults with epilepsy, no identifiable cause can be found. There are 30 marketed antiepileptic drugs, but all possess unwanted CNS side effects. In addition, while therapeutic intervention is possible with marketed compounds, approximately 25% of patients develop refractory epilepsy. These cases are treated with a combination of therapies that are often ineffective.
The neurochemical rationale for treating epileptogenesis resides in our understanding of the multiple factors that contribute to neuronal cell death in this disease (Bengzon et al., 2002). These factors include genetic factors, glutamate-induced excitotoxicty, mitochondrial dysfunction, oxidative stress, growth factor loss and increases in cytokine concentration (Ferriero, 2005). Intense seizure activity produces large increases NMDA-mediated calcium influx (Van Den Pol et al., 1996). High levels of calcium lead to apoptotic cascades that result in acute neuronal cell death. Elevated calcium levels can also generate reactive oxygen species that can produce cell damage and death. In addition, neuronal injury and death have been shown to occur in most epilepsy models and are widely considered both a prerequisite and a result of seizure-induced epilepsy. Two of the processes that contribute to the neural losses are glutamate toxicity and oxidative stress. An emerging concept is that neuroprotection by prevention of glutamate toxicity and oxidative stress will limit both neural damage associated with seizures and provide long-term antiepileptogenesis. The same strategy has been suggested for the treatment of or preventing diseases with excess glutamate in their etiology, including, for example, Parkinson's disease, Alzheimer's, and Huntington's disease.
There is a long felt need for new antiepileptic drugs that are both disease-modifying and effective in treating patients that are refractory to current treatments. There is also a clear and present need for antiepileptic drugs with lower toxicity and higher therapeutic index. The present invention addresses the need to prevent glutamate toxicity and oxidative stress in addition to providing neurostabilization to treat acute seizures and epilepsy. The present invention also addresses the long felt need for new treatments for and means of preventing diseases with excess glutamate in their etiology, including, for example, epilepsy, Parkinson's disease, Alzheimer's, and Huntington's disease.